Host-directed therapeutics

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Host-directed therapeutics, also called host targeted therapeutics, act via a host-mediated response to pathogens rather than acting directly on the pathogen, like traditional antibiotics. They can change the local environment in which the pathogen exists to make it less favorable for the pathogen to live and/or grow. With these therapies, pathogen killing, e.g.bactericidal effects, will likely only occur when it is co-delivered with a traditional agent that acts directly on the pathogen, such as an antibiotic, antifungal, or antiparasitic agent. [1] [2] [3] Several antiviral agents are host-directed therapeutics, and simply slow the virus progression rather than kill the virus. Host-directed therapeutics may limit pathogen proliferation, e.g., have bacteriostatic effects. Certain agents also have the ability to reduce bacterial load by enhancing host cell responses even in the absence of traditional antimicrobial agents. [4] [5] [6]

Contents

Types

Immunomodulatory

Intracellular pathogens often reside in immune cells like macrophages. These pathogens can be obligate or facultative intracellular pathogens. Changing the innate immune response of these host-cells can alter the pathogen's ability to live inside the cell. Many of these immunomodulatory host-directed therapies are adjuvants or pathogen-associated molecular patterns. They can include Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), mannose receptor (MR), dendritic cell-specific intracellular adhesion molecule 3 (ICAM3)-grabbing nonintegrin (DC-SIGN), complement receptors, Fc receptors, and DNA sensors (e.g., STING). Epithelial cells also host pathogens, like Salmonella enterica . These immunomodulatory agents can also alter the epithelial cell environments, since they also have a role in innate signalling.[ citation needed ]

Enhanced host cell function

Autophagy modulators are one type of method to enhance host cell functions. Pathogens like Mycobacterium tuberculosis (MTB), will be degraded in the autophagosome during an effective host response that will clear the bacteria. Because bacteria and other pathogens like MTB can take over cellular responses like autophagy, they can increase their survival in the body. By reactivating effective autophagy processes the pathogen could be cleared. Examples of this has been shown with MTB, [1] and Listeria monocytogenes . [1] OSU-03012 is thought to modulate autophagy in its effect on Salmonella enterica , [7] [8] and Francisella tularensis . [9] [10]

Pathology modification

Modifying lung and macrophage pathology has been shown to have a role in the host-directed therapies for MTB. [1]

Related Research Articles

<i>Salmonella</i> Genus of prokaryotes

Salmonella is a genus of rod-shaped (bacillus) gram-negative bacteria of the family Enterobacteriaceae. The two known species of Salmonella are Salmonella enterica and Salmonella bongori. S. enterica is the type species and is further divided into six subspecies that include over 2,600 serotypes. Salmonella was named after Daniel Elmer Salmon (1850–1914), an American veterinary surgeon.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<i>Cryptococcus neoformans</i> Species of yeast

Cryptococcus neoformans is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to Filobasidiella neoformans. In its yeast state, it is often found in bird excrement. Cryptococcus neoformans can cause disease in apparently immunocompetent, as well as immunocompromised, hosts.

<span class="mw-page-title-main">Autophagy</span> Cellular catabolic process in which cells digest parts of their own cytoplasm

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

<span class="mw-page-title-main">Asymptomatic carrier</span> Organism which has become infected with a pathogen but displays no symptoms

An asymptomatic carrier is a person or other organism that has become infected with a pathogen, but shows no signs or symptoms.

<i>Francisella</i> Genus of bacteria

Francisella is a genus of Gram-negative bacteria. They are small coccobacillary or rod-shaped, nonmotile organisms, which are also facultative intracellular parasites of macrophages. Strict aerobes, Francisella colonies bear a morphological resemblance to those of the genus Brucella. Some Francisella species are pathogenic bacteria but some others are endosymbionts of ticks. Ticks do not use any other food source than vertebrate blood and therefore ingest high levels of protein, iron and salt, but few vitamins. To overcome these nutritional deficiencies, ticks have evolved obligate interactions with nutritional endosymbionts, including Francisella endosymbionts. Their experimental elimination typically results in decreased tick survival, molting, fecundity and egg viability, as well as in physical abnormalities, which all are fully restored with an oral supplement of B vitamins. The genome sequencing of Francisella endosymbionts confirmed that they consistently produce three B vitamin types, biotin (vitamin B7), riboflavin (B2) and folate (B9). Francisella endosymbionts are often misidentified as Francisella tularensis; however, Francisella endosymbionts lack virulence genes and cannot infect humans.

<i>Francisella tularensis</i> Species of bacterium

Francisella tularensis is a pathogenic species of Gram-negative coccobacillus, an aerobic bacterium. It is nonspore-forming, nonmotile, and the causative agent of tularemia, the pneumonic form of which is often lethal without treatment. It is a fastidious, facultative intracellular bacterium, which requires cysteine for growth. Due to its low infectious dose, ease of spread by aerosol, and high virulence, F. tularensis is classified as a Tier 1 Select Agent by the U.S. government, along with other potential agents of bioterrorism such as Yersinia pestis, Bacillus anthracis, and Ebola virus. When found in nature, Francisella tularensis can survive for several weeks at low temperatures in animal carcasses, soil, and water. In the laboratory, F. tularensis appears as small rods, and is grown best at 35–37 °C.

<span class="mw-page-title-main">Opportunistic infection</span> Infection caused by pathogens that take advantage of an opportunity not normally available

An opportunistic infection is an infection caused by pathogens that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune system, an altered microbiome, or breached integumentary barriers. Many of these pathogens do not necessarily cause disease in a healthy host that has a non-compromised immune system, and can, in some cases, act as commensals until the balance of the immune system is disrupted. Opportunistic infections can also be attributed to pathogens which cause mild illness in healthy individuals but lead to more serious illness when given the opportunity to take advantage of an immunocompromised host.

Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. This allows the innate immune system to recognize pathogens and thus, protect the host from infection.

<span class="mw-page-title-main">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

Intracellular parasites are microparasites that are capable of growing and reproducing inside the cells of a host.

<span class="mw-page-title-main">Innate immune system</span> One of the two main immunity strategies

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

<span class="mw-page-title-main">IRGs</span>

Immunity Related Guanosine Triphosphatases or IRGs are proteins activated as part of an early immune response. IRGs have been described in various mammals but are most well characterized in mice. IRG activation in most cases is induced by an immune response and leads to clearance of certain pathogens.

<span class="mw-page-title-main">Plasma gelsolin</span>

Plasma gelsolin (pGSN) is an 83 kDa abundant protein constituent of normal plasma and an important component of the innate immune system. The identification of pGSN in Drosophila melanogaster and C. elegans points to an ancient origin early in evolution. Its extraordinary structural conservation reflects its critical regulatory role in multiple essential functions. Its roles include the breakdown of filamentous actin released from dead cells, activation of macrophages, and localization of the inflammatory response. Substantial decreases in plasma levels are observed in acute and chronic infection and injury in both animal models and in humans. Supplementation therapies with recombinant human pGSN have been shown effective in more than 20 animal models.

<span class="mw-page-title-main">OSU-03012</span> Chemical compound

OSU-03012 (AR-12) is a celecoxib derivative with anticancer and anti-microbial activity. Unlike celecoxib, OSU-03012 does not inhibit COX, but inhibits several other important enzymes instead which may be useful in the treatment of some forms of cancer, When combined with PDE5 inhibitors such as sildenafil or tadalafil, OSU-03012 was found to show enhanced anti-tumour effects in cell culture.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disease. It is a primary immunodeficiency featured by molecular defects in IL12/IFNγ dependent signalling pathway, leading to increased susceptibility to local or disseminated infections by environmental mycobacteria, Mycobacterium bovis Bacille Calmette-Guerin strain, nontyphoidal and typhoidal Salmonella serotypes.

Dipshikha Chakravortty is an Indian microbiologist, molecular pathologist and a professor at the department of Microbiology and Cell Biology at the Indian Institute of Science. Known for her studies on Salmonella and antibacterial resistance, Chakravortty is an elected fellow of the National Academy of Sciences, India, the Indian Academy of Sciences and the Indian National Science Academy. The Department of Biotechnology of the Government of India awarded her the National Bioscience Award for Career Development, one of the highest Indian science awards, for her contributions to biosciences, in 2010.

Kristy M. Ainslie is a Fred Eshelman Distinguished Professor in pharmaceutical science at University of North Carolina at Chapel Hill in the Eshelman School of Pharmacy and chair of the Division of Pharmacoengineering and Molecular Pharmaceutics. She is also joint in the UNC School of Medicine Department of Microbiology and Immunology and affiliated faculty in the UNC/NC State joint Biomedical Engineering department. Additionally, she is part of UNC's Biological and Biomedical Sciences Program (BBSP).

References

  1. 1 2 3 4 Hawn TR, Matheson AI, Maley SN, Vandal O (December 2013). "Host-directed therapeutics for tuberculosis: can we harness the host?". Microbiology and Molecular Biology Reviews. 77 (4): 608–27. doi:10.1128/MMBR.00032-13. PMC   3973381 . PMID   24296574.
  2. ↑ Mahon RN, Hafner R (2017). "Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases". Frontiers in Immunology. 8: 688. doi: 10.3389/fimmu.2017.00688 . PMC   5489679 . PMID   28706516.
  3. ↑ Armstrong-James D, Brown GD, Netea MG, Zelante T, Gresnigt MS, van de Veerdonk FL, Levitz SM (December 2017). "Immunotherapeutic approaches to treatment of fungal diseases". The Lancet. Infectious Diseases. 17 (12): e393–e402. doi:10.1016/S1473-3099(17)30442-5. hdl: 10044/1/57316 . PMID   28774700.
  4. ↑ Yang Z, Bedugnis A, Levinson S, Dinubile M, Stossel T, Lu Q, Kobzik L (September 2019). "Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Penicillin-Susceptible and Penicillin-Resistant Pneumococcal Pneumonia". The Journal of Infectious Diseases. 220 (9): 1498–1502. doi:10.1093/infdis/jiz353. PMC   6761947 . PMID   31287867.
  5. ↑ Ordija CM, Chiou TT, Yang Z, Deloid GM, de Oliveira Valdo M, Wang Z, et al. (June 2017). "Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin". American Journal of Physiology. Lung Cellular and Molecular Physiology. 312 (6): L1018–L1028. doi:10.1152/ajplung.00067.2017. PMC   5495953 . PMID   28385809.
  6. ↑ Yang Z, Chiou TT, Stossel TP, Kobzik L (July 2015). "Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function". American Journal of Physiology. Lung Cellular and Molecular Physiology. 309 (1): L11-6. doi:10.1152/ajplung.00094.2015. PMC   4491512 . PMID   25957291.
  7. ↑ Chiu HC, Kulp SK, Soni S, Wang D, Gunn JS, Schlesinger LS, Chen CS (December 2009). "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrobial Agents and Chemotherapy. 53 (12): 5236–44. doi:10.1128/aac.00555-09. PMC   2786354 . PMID   19805568.
  8. ↑ Hoang KV, Borteh HM, Rajaram MV, Peine KJ, Curry H, Collier MA, et al. (December 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". International Journal of Pharmaceutics. 477 (1–2): 334–43. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  9. ↑ Chiu HC, Soni S, Kulp SK, Curry H, Wang D, Gunn JS, et al. (December 2009). "Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent". Journal of Biomedical Science. 16 (1): 110. doi: 10.1186/1423-0127-16-110 . PMC   2801672 . PMID   20003180.
  10. ↑ Hoang KV, Curry H, Collier MA, Borteh H, Bachelder EM, Schlesinger LS, et al. (April 2016). "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrobial Agents and Chemotherapy. 60 (4): 2052–62. doi:10.1128/AAC.02228-15. PMC   4808193 . PMID   26787696.
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